Drug-induced liver injury in obesity

Many countries are facing an epidemic of obesity that can be explained, at least in part, by a sedentary life style and calorie overconsumption. This poses a major issue for public health since obesity primarily enhances the risk of various illnesses such as type 2 diabetes, coronary heart disease, some cancers and non-alcoholic fatty liver disease (NAFLD). Consequently, obese patients are consuming on average more drugs than non-obese individuals [[1]Stuart B. Lloyd J. Zhao L. Kamal-Bahl S. Obesity, disease burden, and prescription spending by community-dwelling Medicare beneficiaries.Curr Med Res Opin. 2008; 24: 2377-2387Crossref PubMed Scopus (23) Google Scholar]. This could pose another medical issue, in particular for hepatologists, since many drugs are able to induce liver injury [2Porceddu M. Buron N. Roussel C. Labbe G. Fromenty B. Borgne-Sanchez A. Prediction of liver injury induced by chemicals in human with a multiparametric assay on isolated mouse liver mitochondria.Toxicol Sci. 2012; 129: 332-345Crossref PubMed Google Scholar, 3Begriche K. Massart J. Robin M.A. Borgne-Sanchez A. Fromenty B. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.J Hepatol. 2011; 54: 773-794Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar]. Moreover, there is growing evidence that obesity and NAFLD can increase the risk of drug-induced liver injury (DILI), at least for some drugs [3Begriche K. Massart J. Robin M.A. Borgne-Sanchez A. Fromenty B. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.J Hepatol. 2011; 54: 773-794Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, 4Aubert J. Begriche K. Knockaert L. Robin M.A. Fromenty B. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role.Clin Res Hepatol Gastroenterol. 2011; 35: 630-637Crossref PubMed Scopus (200) Google Scholar]. Thus, obese patients could be more prone to develop DILI as a consequence of drug overconsumption and an intrinsic susceptibility of their diseased liver to drug-induced hepatotoxicity. Actually, DILI in obese patients could occur as two distinct clinical settings. Indeed, in the context of obesity and related metabolic diseases, some drugs seem to aggravate pre-existing NAFLD whereas others could induce more frequently an acute hepatitis (Fig. 1). Drugs that could aggravate NAFLD in obese patients are tamoxifen, irinotecan, methotrexate and nucleoside reverse transcriptase inhibitors (NRTIs) such as stavudine and didanosine (Table 1 in Fig. 1) [3Begriche K. Massart J. Robin M.A. Borgne-Sanchez A. Fromenty B. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.J Hepatol. 2011; 54: 773-794Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, 5Farrell G.C. Drugs and steatohepatitis.Semin Liver Dis. 2002; 22: 185-194Crossref PubMed Scopus (185) Google Scholar, 6Lemoine M. Serfaty L. Capeau J. From nonalcoholic fatty liver to nonalcoholic steatohepatitis and cirrhosis in HIV-infected patients: diagnosis and management.Curr Opin Infect Dis. 2012; 25: 10-16Crossref PubMed Scopus (69) Google Scholar, 7Larrain S. Rinella M.E. A myriad of pathways to NASH.Clin Liver Dis. 2012; 16: 525-548Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. Aggravation of NAFLD has also been documented in different animal models with rosiglitazone, tetracycline, phenobarbital and pentoxifylline (Table 1 in Fig. 1) [3Begriche K. Massart J. Robin M.A. Borgne-Sanchez A. Fromenty B. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.J Hepatol. 2011; 54: 773-794Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, 8Massart J. Robin M.A. Noury F. Fautrel A. Lettéron P. Bado A. et al.Pentoxifylline aggravates fatty liver in obese and diabetic ob/ob mice by increasing intestinal glucose absorption and activating hepatic lipogenesis.Br J Pharmacol. 2012; 165: 1361-1374Crossref PubMed Scopus (27) Google Scholar]. Drugs that could induce acute liver injury more often in obese individuals are the volatile halogenated anesthetic halothane and isoflurane, acetaminophen (APAP), and other drugs such as losartan, ticlopidine and omeprazole (Table 1 in Fig. 1) [3Begriche K. Massart J. Robin M.A. Borgne-Sanchez A. Fromenty B. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.J Hepatol. 2011; 54: 773-794Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, 9Gunaratnam N.T. Benson J. Gandolfi A.J. Chen M. Suspected isoflurane hepatitis in an obese patient with a history of halothane hepatitis.Anesthesiology. 1995; 83: 1361-1364Crossref PubMed Scopus (26) Google Scholar, 10Nguyen G.C. Sam J. Thuluvath P.J. Hepatitis C is a predictor of acute liver injury among hospitalizations for acetaminophen overdose in the United States: a nationwide analysis.Hepatology. 2008; 48: 1336-1341Crossref PubMed Scopus (90) Google Scholar, 11Tarantino G. Conca P. Basile V. Gentile A. Capone D. Polichetti G. et al.A prospective study of acute drug-induced liver injury in patients suffering from non-alcoholic fatty liver disease.Hepatol Res. 2007; 37: 410-415Crossref PubMed Scopus (126) Google Scholar]. However, it is noteworthy that the list of drugs in Table 1 is temporary and should expand in the future as DILI in the context of obesity is gaining growing attention. In this “Snapshot” article, I will put forward several potential mechanisms whereby drugs can be more hepatotoxic in obese individuals. Since these mechanisms have mostly been discovered during experimental studies, any extrapolation to humans should be done with caution. Drug-induced worsening of NAFLD could be explained by different mechanisms (Fig. 1B). Regarding fatty liver, some drugs could be able to stimulate lipogenesis in steatotic liver, but not in normal liver, by activating lipogenic transcription factors such as peroxisome proliferator-activated receptor-γ (PPARγ) (e.g. rosiglitazone), pregnane X receptor (e.g. tamoxifen) and carbohydrate response element-binding protein (e.g. pentoxifylline) [3Begriche K. Massart J. Robin M.A. Borgne-Sanchez A. Fromenty B. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.J Hepatol. 2011; 54: 773-794Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, 8Massart J. Robin M.A. Noury F. Fautrel A. Lettéron P. Bado A. et al.Pentoxifylline aggravates fatty liver in obese and diabetic ob/ob mice by increasing intestinal glucose absorption and activating hepatic lipogenesis.Br J Pharmacol. 2012; 165: 1361-1374Crossref PubMed Scopus (27) Google Scholar]. Because numerous drugs are able to alter mitochondrial function [2Porceddu M. Buron N. Roussel C. Labbe G. Fromenty B. Borgne-Sanchez A. Prediction of liver injury induced by chemicals in human with a multiparametric assay on isolated mouse liver mitochondria.Toxicol Sci. 2012; 129: 332-345Crossref PubMed Google Scholar, 3Begriche K. Massart J. Robin M.A. Borgne-Sanchez A. Fromenty B. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.J Hepatol. 2011; 54: 773-794Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar], it is conceivable that impaired mitochondrial fatty acid oxidation (mtFAO) could also be involved in drug-induced aggravation of fatty liver. Importantly, increased FAO during NAFLD is a key adaptive mechanism in order to restrain fat accretion [12Begriche K, Massart J, Robin MA, Bonnet F, Fromenty B. Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology 2013. <http://dx.doi.org/10.1002/hep.26226>.Google Scholar, 13Iozzo P. Bucci M. Roivainen A. Någren K. Järvisalo M.J. Kiss J. et al.Fatty acid metabolism in the liver, measured by positron emission tomography, is increased in obese individuals.Gastroenterology. 2010; 139: 846-856Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar], and thus any impediment to this adaptation could significantly aggravate fatty liver (Fig. 1B). Reduced VLDL secretion could be involved, as several drugs were shown to interfere with VLDL synthesis by inhibiting microsomal triglyceride transfer protein (MTP) activity (e.g. amiodarone, tianeptine) [[14]Lettéron P. Sutton A. Mansouri A. Fromenty B. Pessayre D. Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice.Hepatology. 2003; 38: 133-140Crossref PubMed Scopus (171) Google Scholar] or apolipoprotein B-100 synthesis (e.g. mipomersen) [[15]Visser M.E. Akdim F. Tribble D.L. Nederveen A.J. Kwoh T.J. Kastelein J.J. et al.Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia.J Lipid Res. 2010; 51: 1057-1062Crossref PubMed Scopus (109) Google Scholar] (Fig. 1B). Some drugs are also able to induce oxidative stress [3Begriche K. Massart J. Robin M.A. Borgne-Sanchez A. Fromenty B. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.J Hepatol. 2011; 54: 773-794Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, 16Pessayre D. Mansouri A. Berson A. Fromenty B. Mitochondrial involvement in drug-induced liver injury.Handb Exp Pharmacol. 2010; 196: 311-365Crossref PubMed Scopus (102) Google Scholar], which can trigger the progression of simple steatosis to non-alcoholic steatohepatitis (NASH) (Fig. 1B). Drug-induced oxidative stress could have several origins, in particular through glutathione (GSH) depletion and inhibition of the mitochondrial respiratory chain (MRC) [3Begriche K. Massart J. Robin M.A. Borgne-Sanchez A. Fromenty B. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.J Hepatol. 2011; 54: 773-794Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, 16Pessayre D. Mansouri A. Berson A. Fromenty B. Mitochondrial involvement in drug-induced liver injury.Handb Exp Pharmacol. 2010; 196: 311-365Crossref PubMed Scopus (102) Google Scholar]. The pre-existent reduction of GSH levels and MRC activity in NAFLD [[12]Begriche K, Massart J, Robin MA, Bonnet F, Fromenty B. Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology 2013. <http://dx.doi.org/10.1002/hep.26226>.Google Scholar] could prime drug-induced oxidative stress and accelerate the progression of fatty liver to NASH. Unlike ethanol overconsumption, which is known to aggravate NAFLD [4Aubert J. Begriche K. Knockaert L. Robin M.A. Fromenty B. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role.Clin Res Hepatol Gastroenterol. 2011; 35: 630-637Crossref PubMed Scopus (200) Google Scholar, 17Robin M.A. Demeilliers C. Sutton A. Paradis V. Maisonneuve C. Dubois S. et al.Alcohol increases tumor necrosis factor-α and decreases nuclear factor-κB to activate hepatic apoptosis in genetically obese mice.Hepatology. 2005; 42: 1280-1290Crossref PubMed Scopus (66) Google Scholar], it is still unknown whether drugs able to aggravate NAFLD can stimulate the production of proinflammatory and fibrogenic cytokines such as TNFα and TGFβ, respectively. It is worth mentioning that drug-induced aggravation of NAFLD can also be secondary to the worsening of insulin resistance (IR), a key mechanism leading to hepatic lipid deposition (Fig. 1A). Indeed, worsening of IR exacerbates not only hepatic lipogenesis secondary to hyperinsulinemia but also the delivery of free fatty acids (FFA) to the liver due to adipose triacylglycerol hydrolysis. Drugs known to trigger (or worsen) IR are, for instance, synthetic corticosteroids, antipsychotic drugs (e.g. clozapine, olanzapine), NRTIs, protease inhibitors and thiazide diuretics (e.g. hydrochlorothiazide) [3Begriche K. Massart J. Robin M.A. Borgne-Sanchez A. Fromenty B. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.J Hepatol. 2011; 54: 773-794Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, 5Farrell G.C. Drugs and steatohepatitis.Semin Liver Dis. 2002; 22: 185-194Crossref PubMed Scopus (185) Google Scholar, 6Lemoine M. Serfaty L. Capeau J. From nonalcoholic fatty liver to nonalcoholic steatohepatitis and cirrhosis in HIV-infected patients: diagnosis and management.Curr Opin Infect Dis. 2012; 25: 10-16Crossref PubMed Scopus (69) Google Scholar, 7Larrain S. Rinella M.E. A myriad of pathways to NASH.Clin Liver Dis. 2012; 16: 525-548Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 18Comi R.J. Drug-induced diabetes mellitus.in: LeRoith D. Olefsky J. Taylor S. Diabetes mellitus: a fundamental and clinical text. Lippincott Williams & Wilkins, Philadelphia, PA2004: 880-886Google Scholar]. Higher risk of drug-induced acute hepatitis in obesity could be related to increased activity of several cytochromes P450 (CYPs), which could enhance the generation of toxic metabolites (Fig. 1C). Indeed, increased activity of several CYPs such as CYP1A2, CYP2C9, CYP2D6 and CYP2E1 has been documented in obese individuals [4Aubert J. Begriche K. Knockaert L. Robin M.A. Fromenty B. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role.Clin Res Hepatol Gastroenterol. 2011; 35: 630-637Crossref PubMed Scopus (200) Google Scholar, 19Brill M.J. Diepstraten J. van Rongen A. van Kralingen S. van den Anker J.N. Knibbe C.A. Impact of obesity on drug metabolism and elimination in adults and children.Clin Pharmacokinet. 2012; 51: 277-304Crossref PubMed Scopus (259) Google Scholar]. Higher CYP2E1 activity could explain why drugs such as halothane and APAP seem to be more hepatotoxic in the context of obesity and NAFLD since CYP2E1 transforms these drugs into the highly reactive metabolites trichloroacetyl chloride and N-acetyl-p-benzoquinone imine (NAPQI), respectively [4Aubert J. Begriche K. Knockaert L. Robin M.A. Fromenty B. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role.Clin Res Hepatol Gastroenterol. 2011; 35: 630-637Crossref PubMed Scopus (200) Google Scholar, 20Aubert J. Begriche K. Delannoy M. Morel I. Pajaud J. Ribault C. et al.Differences in early acetaminophen hepatotoxicity between obese ob/ob and db/db mice.J Pharmacol Exp Ther. 2012; 342: 676-687Crossref PubMed Scopus (52) Google Scholar]. When generated in excess, these reactive metabolites can induce hepatic oxidative stress, severe mitochondrial dysfunction and cytolysis (Fig. 1C) [4Aubert J. Begriche K. Knockaert L. Robin M.A. Fromenty B. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role.Clin Res Hepatol Gastroenterol. 2011; 35: 630-637Crossref PubMed Scopus (200) Google Scholar, 20Aubert J. Begriche K. Delannoy M. Morel I. Pajaud J. Ribault C. et al.Differences in early acetaminophen hepatotoxicity between obese ob/ob and db/db mice.J Pharmacol Exp Ther. 2012; 342: 676-687Crossref PubMed Scopus (52) Google Scholar]. It is noteworthy that higher risk of APAP-induced acute liver injury in obese individuals with NAFLD is mostly suspected in the context of APAP overdose [10Nguyen G.C. Sam J. Thuluvath P.J. Hepatitis C is a predictor of acute liver injury among hospitalizations for acetaminophen overdose in the United States: a nationwide analysis.Hepatology. 2008; 48: 1336-1341Crossref PubMed Scopus (90) Google Scholar, 21Myers R.P. Shaheen A.A. Hepatitis C, alcohol abuse, and unintentional overdoses are risk factors for acetaminophen-related hepatotoxicity.Hepatology. 2009; 49: 1399-1400Crossref PubMed Scopus (26) Google Scholar], although therapeutic doses of this pain killer could also be involved [[22]Forget P. Wittebole X. Laterre P.F. Therapeutic dose of acetaminophen may induce fulminant hepatitis in the presence of risk factors: a report of two cases.Br J Anaesth. 2009; 103: 899-900Crossref PubMed Scopus (27) Google Scholar]. Another mechanism that could explain higher risk of drug-induced acute hepatitis in obesity is reduced levels of GSH, in particular at the mitochondrial level [[12]Begriche K, Massart J, Robin MA, Bonnet F, Fromenty B. Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology 2013. <http://dx.doi.org/10.1002/hep.26226>.Google Scholar], which could impair the removal of CYP-generated reactive metabolites (Fig. 1C). Because obesity is associated with reduced activity of some CYPs such as CYP3A4 [[19]Brill M.J. Diepstraten J. van Rongen A. van Kralingen S. van den Anker J.N. Knibbe C.A. Impact of obesity on drug metabolism and elimination in adults and children.Clin Pharmacokinet. 2012; 51: 277-304Crossref PubMed Scopus (259) Google Scholar], higher risk of acute hepatitis is not expected with all drugs able to generate toxic metabolites. Moreover, enhanced glucuronosyltransferase activity seems to be common in obesity [19Brill M.J. Diepstraten J. van Rongen A. van Kralingen S. van den Anker J.N. Knibbe C.A. Impact of obesity on drug metabolism and elimination in adults and children.Clin Pharmacokinet. 2012; 51: 277-304Crossref PubMed Scopus (259) Google Scholar, 20Aubert J. Begriche K. Delannoy M. Morel I. Pajaud J. Ribault C. et al.Differences in early acetaminophen hepatotoxicity between obese ob/ob and db/db mice.J Pharmacol Exp Ther. 2012; 342: 676-687Crossref PubMed Scopus (52) Google Scholar], which may favor the detoxication of some compounds. Finally, it is also noteworthy that under-dosing is expected with drugs whose dosage is not adapted to higher body mass index. Clearly, more investigations are needed in order to decipher the mechanisms whereby some drugs are more toxic on the obese liver. From a clinical viewpoint, a better identification of the drugs presenting such harmful effects is urgently warranted. This should prompt physicians to carry out a regular monitoring of liver function in obese patients treated with these drugs in order to detect any deterioration of the pre-existing NAFLD, or the occurrence of acute hepatitis. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.